A calcium phosphate cement (CPC), developed under this research project, was approved by the FDA in 1996 for cranial defects repair applications in humans, thus becoming the first material of its kind to be available for clinical use. While CPCs were shown to be very useful in a number of dental and medical applications for which other materials do not work well, in vivo study results suggest that in order to achieve the best results, CPC should have handling and in vivo properties that are best suited for the particular clinical application. The objectives of the proposed research are to elucidate mechanisms of cement setting reactions and to understand the physicochemical factors that influence cements= handling and in vivo properties. Four specific aims are proposed. Aim 1 proposes to understand factors that control the hydrolysis reactions of tetracalcium phosphate (TTCP), alpha-tricalcium phosphate (alpha-TCP), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA) and calcium hydroxide. These calcium phosphate salts are the major components of different CPCs. Hydrolysis of one or more of the salts that form hydroxyapatite (HA) is responsible for the hardening of the cement. A better understanding of the hydrolysis reaction of each of these salts will provide important insights into factors that influence some important cement properties, including the rate of conversion to HA, formation of Ca-deficient or stoichiometric HA, the crystallinity HA, etc. Defective or non-stoichiometric HAs are believed to be more bioresorbable. Aim 2 proposes to study the dissolution rate of cement products in demineralizing solutions having ionic compositions mimicking the acidic environment produced by osteoclasts. A dual constant-composition titration system was developed during the report period for measuring dissolution rates of calcium phosphate biomaterials under simulated acidified physiological solutions. The Principal Investigator proposes to use this technique as an in vitro model for predicting resorption rates of CPC and to understand factors that control the dissolution rate. Aim 3 proposes to study properties of non-rigid and resorbable calcium phosphate cements. Experiments are described to study composites of CPC and chitosan, a biocompatible polymer to form self-hardening, bioresorbable, and non-rigid bone graft materials. These materials should be useful in a number of applications in which the implant can remain stable and firmly attached to the bone defect surface despite micro-movements of the defect walls. Aim 4 will study properties of injectable premixed calcium phosphate cement pastes. Premixed CPC pastes have the advantages that they are stable in the package and harden only after delivery to the defect site where the non-aqueous liquid is replaced by water from the surrounding tissue. While premixed CPC is considerably easier to use and is injectable, its properties are quite different from the conventional CPCs. The hardening time, resistance to washout, and HA conversion of premixed pastes consisting of CPC powder and non-aqueous liquids, such as glycerin, will be studied. The Principal Investigator also proposes to determine mechanical properties of the hardened CPC pastes.